Recently, arteriosclerotic diseases are increasing due to changes of life-style as a result of improvement in living standards such as ingestion of a high-calorie diet and a high-cholesterol diet, lack of exercise, obesity, stress caused by social complexities, aging society, and the like. Risk factors of arteriosclerotic diseases can be classified into smoking, obesity, hypertension, hyperuricemia, diabetes mellitus, hyperlipidemia, and the like. Among them, hyperlipidemia such as hypertriglyceridemia, hypo-HDL (HDL: high-density lipoprotein) and hyper-LDL (LDL: low-density lipoprotein) draws increasing attention, and particularly lowering hyper-cholesterol level is placed emphasis as an object for the pharmacotherapy, and various treatments have been performed. In particular, a drug (statin drug), which can achieve significant results in treatment of hypercholesterolemia, is the drug inhibiting HMG-CoA (HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A) reductase, a rate-limiting enzyme of cholesterol biosynthesis, can be mentioned. Cholesterol lowering therapy using statin shows successful results specifically in various arteriosclerotic diseases, for example myocardial infarction and cerebral infarction, caused by hyperlipidemia. With regard to coronary arterial diseases including acute myocardial infarction, results of multicenter epidemiological surveys such as 4S (Scandinavian Simvastatin Survival Study) and WOS (COPS) (West of Scotland Coronary Prevention Study) were reported, and effectiveness of simvastatin therapy has been proven in an improvement of survival rate for five years. However, even if the statin drug represented by simvastatin (Patent Reference 1) and pravastatin (Patent Reference 2) is said to be effective, improvement rate for rate of crisis of coronary disease event is no more than about 30%, and is not satisfactory condition in the medical field. As a mechanism for development of drug efficacy with the statin, it is known that as a result of generating the inhibition of cholesterol biosynthesis in vivo and simultaneously occurring increased expression of LDL receptors accompanied by lowering cholesterol level in the liver, the increased LDL receptors promote incorporation of blood LDL and cause to decrease total cholesterol level in plasma. Consequently, there is a problem that complete lowering LDL cholesterol cannot be expected in patients with homozygote and heterozygote who are deficient of LDL receptor such as familial hypercholesterolemia. It is known that combined medication of fibrate and statin to the patient with hypertriglyceridemia causes rhabdomyolysis, and in case of cerivastatin (Patent Reference 3), severe side effect caused by such the medication resulted to discontinuation of sales. Considering such background, drugs, which do not exhibit anti-arteriosclerotic action coupled with lowering total cholesterol level in plasma but exhibit direct action to arteriosclerosis lesion, is attractive and to be expected.
Plaques, which are the primary focus of atherosclerosis, consist of the lipid core filled with cholesterol and ester thereof and the fibrous material called extracellular matrix. Among the plaques, lipid-rich plaques, which are predominantly made up of lipid and inflammatory cells such as macrophage and covered with thin fibrous membrane, are called “unstable plaques”. It is easy to rupture, and when the plaques rupture, contents of the plaques are exposed to the blood flow to promote thrombogenesis. As a result, acute coronary syndrome (ACS) such as unstable angina, acute myocardial infarction and ischemic sudden death will occur (Non-Patent Reference 1). Actually, it is known that as a result of examination of culprit lesion in the cases of death caused by ACS, about 75% of the cases were due to thrombogenesis accompanied by rupture of the plaques (Non-Patent Reference 2). Focusing attention on stenotic rate of blood vessel, i.e. plaque size, the culprit lesion of myocardial infarction was found mainly to be the region of blood vessel with the stenotic rate below 50% (Non-Patent Reference 2). This fact suggests that causes for plaque rupture are not the size of the plaque size but the quality of the plaque.
Involvement of matrix metalloprotease (MMP) secreted by the large amount of accumulated macrophage is considered to be direct cause for the plaque rupture, and MMP may degrade the fibrous collagen to thin and weaken the fibrous film. Further, the macrophage is reported to stimulate the thrombogenesis at the ruptured region through expression of the tissue factor (Non-Patent Reference 3).
Consequently, prevention of the rupture of “unstable plaques” may be important in countermeasure for ACS. For that purpose, methods including inhibition of the function or the accumulation of macrophages, or inhibition of the degradation of the fibrous collagen or strengthening the fibrous cap by increasing the collagen content may be considered. In conclusion for prevention and treatment of acute coronary syndrome, although regression of the plaques accompanied by reducing total cholesterol level in plasma may be effective, instead drugs for inhibiting accumulation of the macrophage and increasing the collagen, as a result, stabilizing lipid-rich plaques may be more preferable.
Considering these situations, acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitor has been drawn attention as cholesterol lowering drug having different mechanism of action to the statin.
Although there are large numbers of reports indicating regression of plaques by using ACAT inhibitor, significant decrease in plasma total cholesterol level is accompanied in any cases. Consequently, it is unknown whether direct regression of plaques could be achieved or not, and as a result, there may be discrepancy in interpretation of data (Non-Patent References 4 and 5).
However, recently, several ACAT inhibitors, which show regression effect of plaques without affecting the plasma total cholesterol level, have reported. For example, JP-A-2002-255808 (Patent Reference 4) discloses ACAT inhibitor as a plaque regressing agent. WO 01/034127 (Patent Reference 5) discloses ACAT inhibitor, which leads to decrease accumulation of macrophage and expression of MMP in the plaques. However, although the plaque reducing activities were indicated in these reports, they fail to mention increase or decrease of the collagen, one of important factor contributing to the stability of the plaques (Non-Patent Reference 6). Although the compound (avasimibe, hereinafter designated as CI-1011) examined therein exhibits plaque regressing activity, no finding such as increase of collagen and stability is indicated.
As obvious from above, ACAT inhibitor, which is different from conventional ACAT inhibitors, and independently reduces the occupation rate of macrophages in the plaques without affecting the plasma total cholesterol level and has action to increase the occupation rate of collagen as well as preventing rupture of the plaques without leading to diffuse macrophages even if they are ruptured. Such ACAT inhibition has not been known.    Patent Reference 1: U.S. Pat. No. 4,444,784.    Patent Reference 2: U.S. Pat. No. 4,346,227.    Patent Reference 3: U.S. Pat. No. 5,177,080.    Patent Reference 4: JP-A-2002-255808.    Patent Reference 5: WO 01-034127.    Non-Patent Reference 1: N. Engl. J. Med. 326(4): 242-50, 1992.    Non-Patent Reference 2: Circulation 92(3): 657-71, 1995.    Non-Patent Reference 3: Ann. N.Y. Acad. Sci. 902:140-52, 2000.    Non-Patent Reference 4: Exp. Opin. Invest. Drugs 4: 353-387, 1995.    Non-Patent Reference 5: Drug Discovery Today 3: 19-25, 1998.    Non-Patent Reference 6: Circ. Res. 86: 101-8, 2000.